DESCRIPTION Previous studies from our laboratory have demonstrated that susceptibility to atherosclerosis differs significantly between inbred strains of mice, suggesting a strong genetic component to the disease. Athl is a quantitative trait locus that we found to be associated with decreased plasma HDL-cholesterol levels and increased atherosclerotic lesion formation in susceptible strains of mice when fed a high fat diet. We have recently identified a Athl candidate gene, Aop2, which is a member of the thiol-specific antioxidant family. We believe Aop2 mediates protection from atherosclerosis based on its chromosomal co-localization with Athl, mRNA induction by high fat diet, amino acid and expression differences between resistant and susceptible strains, and the proposed role of LDL oxidation in the pathogenesis of atherosclerosis. I propose three specific aims toward the characterization of AOP2 in atherosclerosis resistance: 1) obtain definitive proof that AOP2 confers resistance to atherosclerosis by transgenic rescue; 2) characterize expression of AOP2 in the arterial wall; and 3) determine the molecular basis for the regulatory differences observed between atherosclerosis resistant and susceptible strains.